Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Prognostic Significance of Overexpression of EZH2 and H3k27me3 Proteins in Gastric Cancer

  • He, Long-Jun (The State Key Laboratory of Oncology in South China) ;
  • Cai, Mu-Yan (The State Key Laboratory of Oncology in South China) ;
  • Xu, Guo-Liang (The State Key Laboratory of Oncology in South China) ;
  • Li, Jian-Jun (The State Key Laboratory of Oncology in South China) ;
  • Weng, Zi-Jin (Department of Gastroenterology, the First Affiliated Hospital, Sun Yat-sen University) ;
  • Xu, Da-Zhi (The State Key Laboratory of Oncology in South China) ;
  • Luo, Guang-Yu (The State Key Laboratory of Oncology in South China) ;
  • Zhu, Sen-Lin (Department of Pathology, the Third Affiliated Hospital, Sun Yat-sen University) ;
  • Xie, Dan (The State Key Laboratory of Oncology in South China)
  • Published : 2012.07.31
Download PDF
⟨ Previous Next ⟩

Abstract

The enhancer of zeste homolog 2 (EZH2) methyl transferase and histone 3 lysine 27 (H3K27me3) protein can repress gene transcription, and their aberrant expression has been observed in various human cancers. This study determined their expression levels in gastric cancer tissues with reference to clinicopathological features and patient survival. We collected 117 gastric cancer and corresponding normal tissues for immunohistochemistry analysis. In gastric cancers, 82/117 (70.1%) were positive for EZH2 and 66/117 (56.4%) for H3K27me3 proteins in contrast to only 5.41% and 7.25% of normal gastric mucosa specimens, respectively. Kaplan-Meier survival data showed the average overall and disease-free survival of EZH2 high expression patients was 25.2 and 20.2 months, respectively, shorter than that with EZH2 low expression (40.5 and 35.9 months). The average overall survival and disease-free survival of high H3K27me3 expression patients was 23.4 and 17.4 months, shorter than without H3K27me3 expression (37.6 and 34.5 months). The average overall survival and disease-free survival of patients with both EZH2 and H3K27me3 expression was 18.8 and 12.9 months, respectively, shorter than that with either alone (34.7 and 31.2 months) or with low levels of both (43.9 and 39.9 months). Multivariate Cox regression analysis showed that H3K27me3 and EZH2 expression, tumor size differentiation and clinical stage were all independent prognostic factors for predicting patient survival. This study demonstrated that detection of both EZH2 and H3K27me3 proteins can predict poor survival of gastric cancer patients, superior to single protein detection. In addition, H3K27me3 and EZH2 protein expression could predict lymph node metastasis.

Keywords

References

  1. Bachmann IM, Halvorsen OJ, Collett K, et al (2006). EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol, 24, 268-73.
  2. Bryant RJ, Cross NA, Eaton CL, Hamdy FC, Cunliffe VT (2007). EZH2 promotes proliferation and invasiveness of prostate cancer cells. Prostate, 67, 547-56. https://doi.org/10.1002/pros.20550
  3. Cai MY, Hou JH, Rao HL, et al (2011). High expression of H3K27me3 in human hepatocellular carcinomas correlates closely with vascular invasion and predicts worse prognosis in patients. Mol Med, 17, 12-20.
  4. Cai MY, Tong ZT, Zheng F, et al (2011). EZH2 protein: a promising immunomarker for the detection of hepatocellular carcinomas in liver needle biopsies. Gut, 60, 967-76. https://doi.org/10.1136/gut.2010.231993
  5. Cai MY, Tong ZT, Zhu W, et al (2011). H3K27me3 protein is a promising predictive biomarker of patients' survival and chemoradioresistance in human nasopharyngeal carcinoma. Mol Med, 17, 1137-45.
  6. Cao R, Wang L, Wang H, et al (2002). Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science, 298, 1039-43. https://doi.org/10.1126/science.1076997
  7. Collett K, Eide GE, Arnes J, et al (2006). Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer. Clin Cancer Res, 12, 1168-74. https://doi.org/10.1158/1078-0432.CCR-05-1533
  8. Esteller M (2008). Epigenetics in cancer. N Engl J Med, 358, 1148-59. https://doi.org/10.1056/NEJMra072067
  9. Green D, de Leon S P, Leon-Rodriguez E, Sosa-Sanchez R (2000). Adenocarcinoma of the stomach: univariate and multivariate analysis of factors associated with survival. Am J Clin Oncol, 25, 84-9.
  10. Harrison LE, Karpeh MS, Brennan MF (1998). Extended lymphadenectomy is associated with a survival benefit for node-negative gastric cancer. J Gastrointest Surg, 2, 126-31. https://doi.org/10.1016/S1091-255X(98)80002-4
  11. He LR, Liu MZ, Li BK, et al (2009). Prognostic impact of H3K27me3 expression on locoregional progression after chemoradiotherapy in esophageal squamous cell carcinoma. BMC Cancer, 9, 461. https://doi.org/10.1186/1471-2407-9-461
  12. He LR, Liu MZ, Li BK, et al (2010). High expression of EZH2 is associated with tumor aggressiveness and poor prognosis in patients with esophageal squamous cell carcinoma treated with definitive chemoradiotherapy. Int J Cancer, 127, 138-47. https://doi.org/10.1002/ijc.25031
  13. Maruyama K, Sasako M, Kinoshita T (1992). Wert der systematischen erweiterten Lymphknotendissektion--Ergebnisse in Japan. [Value of systematic extended lymph node dissection--results in Japan]. Langenbecks Arch Chir Suppl Kongressbd, 1992, 130-5.
  14. Matsukawa Y, Semba S, Kato H, et al (2006). Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer. Cancer Sci, 97, 484-91. https://doi.org/10.1111/j.1349-7006.2006.00203.x
  15. Msika S, Benhamiche AM, Jouve JL, Rat P, Faivre J (2000). Prognostic factors after curative resection for gastric cancer. A population-based study. Eur J Cancer, 36, 390-6. https://doi.org/10.1016/S0959-8049(99)00308-1
  16. Rao ZY , Cai MY , Yang GF, et al (2010). EZH2 supports ovarian carcinoma cell invasion and/or metastasis via regulation of TGF-beta1 and is a predictor of outcome in ovarian carcinoma patients. Carcinogenesis, 31, 1576-83. https://doi.org/10.1093/carcin/bgq150
  17. Schlesinger Y, Straussman R, Keshet I, et al (2007). Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet, 39, 232-6. https://doi.org/10.1038/ng1950
  18. Strahl BD, Allis CD (2000). The language of covalent histone modifications. Nature, 403, 41-5. https://doi.org/10.1038/47412
  19. Tonini T, D'Andrilli G, Fucito A, Gaspa L, Bagella L (2008). Importance of Ezh2 polycomb protein in tumorigenesis process interfering with the pathway of growth suppressive key elements. J Cell Physiol, 214, 295-300. https://doi.org/10.1002/jcp.21241
  20. Tzao C, Tung HJ, Jin JS, et al (2009). Prognostic significance of global histone modifications in resected squamous cell carcinoma of the esophagus. Mod Pathol, 22, 252-60. https://doi.org/10.1038/modpathol.2008.172
  21. Weikert S, Christoph F, Kollermann J, et al (2005). Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int J Mol Med, 16, 349-53.
  22. Wei Y, Xia W, Zhang Z, et al (2008). Loss of trimethylation at lysine 27 of histone H3 is a predictor of poor outcome in breast, ovarian, and pancreatic cancers. Mol Carcinog, 47, 701-6. https://doi.org/10.1002/mc.20413
  23. Widschwendter M, Fiegl H, Egle D, et al (2007). Epigenetic stem cell signature in cancer. Nat Genet, 39, 157-8. https://doi.org/10.1038/ng1941
  24. Yasui W, Yokozaki H, Fujimoto J, et al (2000). Genetic and epigenetic alterations in multistep carcinogenesis of the stomach. J Gastroenterol, 35, 111-5.
  25. Yasui W, Oue N, Kuniyasu H, et al (2001). Molecular diagnosis of gastric cancer: present and future. Gastric Cancer, 4, 113-21. https://doi.org/10.1007/PL00011733
  26. Yonemitsu Y, Imazeki F, Chiba T, et al (2009). Distinct expression of polycomb group proteins EZH2 and BMI1 in hepatocellular carcinoma. Hum Pathol, 40, 1304-11. https://doi.org/10.1016/j.humpath.2009.01.017
  27. Yu J, Yu J, Rhodes DR, et al (2007). A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. Cancer Res, 67, 10657-63. https://doi.org/10.1158/0008-5472.CAN-07-2498

Cited by

  1. MicroRNA-101 inhibits the metastasis of osteosarcoma cells by downregulation of EZH2 expression vol.32, pp.5, 2014, https://doi.org/10.3892/or.2014.3459
  2. Role of EZH2 protein expression in gastric carcinogenesis among Asians: a meta-analysis vol.35, pp.7, 2014, https://doi.org/10.1007/s13277-014-1888-y
  3. Enhancer of Zeste Homolog 2 as an Independent Prognostic Marker for Cancer: A Meta-Analysis vol.10, pp.5, 2015, https://doi.org/10.1371/journal.pone.0125480
  4. Macrophage migration inhibitory factor as a potential prognostic factor in gastric cancer vol.21, pp.34, 2015, https://doi.org/10.3748/wjg.v21.i34.9916
  5. SUZ12 promotes gastric cancer cell proliferation and metastasis by regulating KLF2 and E-cadherin vol.36, pp.7, 2015, https://doi.org/10.1007/s13277-015-3195-7
  6. Nomogram Incorporating CD44v6 and Clinicopathological Factors to Predict Lymph Node Metastasis for Early Gastric Cancer vol.11, pp.8, 2016, https://doi.org/10.1371/journal.pone.0159424
  7. Prognostic significance of EZH2 expression in patients with oesophageal cancer: a meta-analysis vol.20, pp.5, 2016, https://doi.org/10.1111/jcmm.12791
  8. Interference with endogenous EZH2 reverses the chemotherapy drug resistance in cervical cancer cells partly by up-regulating Dicer expression vol.37, pp.5, 2016, https://doi.org/10.1007/s13277-015-4416-9
  9. The novel EZH2 inhibitor, GSK126, suppresses cell migration and angiogenesis via down-regulating VEGF-A vol.77, pp.4, 2016, https://doi.org/10.1007/s00280-016-2990-1
  10. Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor vol.108, pp.10, 2017, https://doi.org/10.1111/cas.13326
  11. The role of histone modifications and telomere alterations in the pathogenesis of diffuse gliomas in adults and children vol.132, pp.1, 2017, https://doi.org/10.1007/s11060-016-2349-9
  12. Methylation modification in gastric cancer and approaches to targeted epigenetic therapy (Review) vol.50, pp.6, 2017, https://doi.org/10.3892/ijo.2017.3981
  13. Circulating Nucleosomes and Nucleosome Modifications as Biomarkers in Cancer vol.9, pp.1, 2017, https://doi.org/10.3390/cancers9010005
  14. Development of a high-throughput fluorescence polarization assay for the discovery of EZH2-EED interaction inhibitors pp.1745-7254, 2018, https://doi.org/10.1038/aps.2017.59
  15. How to stomach an epigenetic insult: the gastric cancer epigenome pp.1759-5053, 2017, https://doi.org/10.1038/nrgastro.2017.53
  16. Role of epigenetics in EBV regulation and pathogenesis vol.9, pp.6, 2014, https://doi.org/10.2217/fmb.14.41
  17. Notable roles of EZH2 and DNMT1 in epigenetic dormancy of the SHP1 gene during the progression of chronic myeloid leukaemia vol.13, pp.6, 2017, https://doi.org/10.3892/ol.2017.6050
  18. Long non-coding RNA PVT1 facilitates cell proliferation by epigenetically regulating FOXF1 in breast cancer vol.8, pp.5, 2018, https://doi.org/10.1039/C7RA12042G
  19. Prognostic role of EZH2 in gliomas: a meta-analysis vol.33, pp.1, 2018, https://doi.org/10.5301/ijbm.5000293
  20. Targeting epigenetics using synthetic lethality in precision medicine vol.75, pp.18, 2018, https://doi.org/10.1007/s00018-018-2866-0